1. Field of the Invention
The present invention relates to the preparation of an injectable paste from powdery calcium sulfate based bone cement compositions and a medicament, which compositions are made ready to use, by mixing with an aqueous liquid and further to the manufacture of antibiotic beads and the use thereof for treatment of osteomyelitis.
Introduction
The life expectancy of the world population has increased tremendously during the last 50 years, and according to the forecasts there will be more people over 60 years of age than less than twenty years of age in Europe.
More people will need medical help for diseases related to age, which will increase the pressure of the hospitals.
Bone is the second most common material to be transplanted after blood. The most reliable method to repair bone defects is to use autogenous bone, i.e. bone taken from another site in the body. However, problems may occur at the second surgical site from where the graft is taken. To avoid these extra trauma allograft can be used i.e. bone graft between individuals of the same species. Allograft has a lower osteogenic capacity than autograft and the rate of new bone formation might be lower. They also have a higher resorption rate, a larger immunogenic response and less revascularisation of the recipient. Allograft must also be controlled for viruses since they can transfer, for example, HIV and hepatitis. The use of allograft is now the most common method for bone transplantation and repairing of bone defects. To solve the problems of supply, unpredictable strength and risk of infection, synthetic bone substitutes have become a realistic alternative. Thus, the demand for and use of synthetic bone substitutes is increasing rapidly.
Calcium sulfate hemihydrate, CaSO.½H2O, CSH, was one of the first materials investigated as a substitute for bone grafts. Calcium sulfate hemihydrate implanted in areas of subcortical bone produces no further untoward reaction in the tissue than normally is present in a fracture. The new bone growing into calcium sulfate is normal bone, and no side effects attributable to the implantation of calcium sulfate hemihydrate have been noted in adjacent tissues or in distant organs.
The most important advantage with calcium sulfate is its excellent biocompatibility. The drawbacks are the rapid resorption and low strength, which makes it less useful in larger or non-contained defects and when the fracture healing exceeds 4-6 weeks.
When calcium sulfate hemihydrate is mixed with water, it will hydrate to calcium sulfate dihydrate, CSD, according to the below reaction scheme (1):CaSO4.0.5H2O+1.5H2O=>CaSO4.2H2O+Heat  (1)
The hydration reaction of calcium sulfate hemihydrate can be summarized in three phases.                1) The induction period starting immediately after the calcium sulfate hemihydrate powder is mixed with water. The calcium sulfate hemihydrate then dissolves and the solution becomes supersaturated with respect to calcium and sulfate ions. This leads to precipitation of the less soluble calcium sulfate dihydrate, CSD. In order for the hydration reaction to be able to proceed, these CSD nuclei have to have a radius that is larger than a “critical radius” (determined for each specific system). The induction period is critical for the hydration reaction and any disturbances in the solubility of calcium sulfate hemihydrate or growth of CSD-crystals in this phase will delay the further hydration reaction to a higher degree than occurrence of the same disturbance in later phase of the process.        2) The acceleratory or growth period starts when a sufficient number of CSD crystals have reached the critical size for them to act as nucleating embryos. The CSD nucleus formed will then grow and form large crystals. The crystals will eventually be sufficiently large to interlock with each other and the friction between crystals contributes to the strength of the formed material.        3) The third phase is relatively slow and consists of the completion of the hydration of the calcium sulfate hemihydrate as stated in N. B. Singh and B. Middendorf, Calcium sulphate hemihydrate hydration leading to gypsum crystallization, Progress in Crystal Growth and Characterization of Materials 53 (2007) 57-77 and as illustrated in FIG. 1 in the form of a schematic view showing the fraction of hydrated calcium sulfate dihydrate as a function of time.        
For a variety of applications, it is desired to be able to mix different additives to calcium sulfate based bone cements. Bone substitutes comprising an antibiotic content are often requested to prevent or treat osteomyelitis (bone infections) (Steven Gitelis and Gregory T. Brebach, The treatment of chronic osteomyelitis with a biodegradable antibiotic implant, Journal of Orthopaedic Surgery 2002 10(1): 53-60).
Several non-biodegradable and biodegradable antibiotic cement delivery systems are available for the delivery of antibiotics for adjunctive therapy in the management of osteomyelitis. A major representative of the non-biodegradable delivery system includes the polymethyl methacrylate (PMMA) beads. Antibiotics that can be incorporated into this delivery system are however limited to the heat stable antibiotics such as vancomycin and the amino glycosides; tobramycin being the more popular.
However, it has been found that addition of various additives such as bioactive agents, e.g. an antioxidant, a vitamin, a hormone, antibiotics a cytostatic, a bisphosphonate, a growth factor, or a protein or peptide or a bone marrow aspirate or demineralised bone, to bone cement compositions based on calcium sulfate hemihydrate often interferes with or even prevents the hardening process thereof. The retarding effect on the hardening has been found to be dependent of the identity of the additive and the specific bone mineral substitute composition.
Thus it has been found (Steven Gitelis and Gregory T. Brebach, ibid) that addition of antibiotics may retard or accelerate the hydration of calcium sulfate hemihydrate into calcium sulfate dihydrate significantly, or even prevent completion of the hydration and consequently, the hydraulic cement may no longer be suitable for use in clinical applications since its properties are significantly changed by the addition of the antibiotic. The incomplete/slow CSH hydration affects different properties of the final material and excludes a number of applications for the material.
2. Description of the Related Art
Various bone cement compositions comprising ceramics hardening in vivo upon contact with water or body fluids and comprising a medicament have been disclosed.
WO 2004/078223 (Lidgren) discloses a bone mineral substitute material comprising a calcium phosphate component and hardened calcium sulphate and an additive such as an antioxidant, a vitamin, a hormone, an antibiotic, a cytostatic, a bisphosphonate, a growth factor, or a protein. The additive can be included in the particulate hardened calcium sulfate during its preparation or included in the sterile aqueous liquid of the composition, and in the experiments a slow release of iohexyl or gentamycin was found when the additive was included in the particulate hardened calcium sulfate during its preparation.
In N. B. Singh and B. Middendorf, Calcium sulphate hemihydrate hydration leading to gypsum crystallization, Progress in Crystal Growth and Characterization of Materials 53 (2007) 57-77 it is disclosed that the presence of e.g. carboxylic acids retards the growth of gypsum crystals during hemihydrate hydration.
Richelsoph et al, Elution Behavior of Daptomycin-loaded Calcium Sulfate Pellets, CLINICAL ORTHOPAEDICS AND RELATED RESEARCH, Number 461, pp 68-73, found that antibiotics often tend to disturb the setting of calcium sulphate hemihydrate and that when adding daptomycin the CSH did not harden, and incorporation of traditional accelerant techniques (addition of a small percentage of calcium sulphate dihydrate, addition of saline, increasing the temperature and decreasing the water content) all failed to improve the setting characteristics. Furthermore, Richelsoph found that when using potassium sulfate as accelerator a suitable pellet was produced and describes a two-step method in which calcium sulfate hemihydrate powder and a potassium sulfate solution were stirred vigorously for two minutes and allowed to rest for additionally one minute before daptomycin was added.
The hydration of calcium sulfate hemihydrate, CSH, into calcium sulfate dihydrate, CSD, may be retarded or prevented from being completed. This may lead to the result that the hydraulic cement will no longer be suitable for use in clinical applications since its properties are significantly changed by addition of an antibiotic. The incomplete/slow CSH hydration affects different properties of the final material and excludes the use of such a material for a number of applications. Accelerated hydration has also been reported when adding antibiotics, which leads to similar limitations.
WO 02/05861 discloses an injectable composition for a bone mineral substitute material, which comprises a dry powder mixed with an aqueous liquid, said powder comprising a first reaction component comprising a calcium sulphate hemihydrate with the capability of being hardened to calcium sulphate dihydrate when reacting with said aqueous liquid; a second reaction component, which comprises a calcium phosphate with the capability of being hardened to a calcium phosphate cement when reacting with said aqueous liquid; and at least one accelerator for the reaction of said first and/or second reaction component with said aqueous liquid. WO 02/05861 does not disclose any specific compositions comprising an additive having a retarding effect on the hardening of the inorganic bone mineral substitute composition when admixed together with an aqueous liquid or any measure to counteract such retardation of the hardening of the composition.
U.S. Pat. No. 6,251,139 discloses a method of using a plaster of Paris as an orthopedic filling material prepared by mixing 15-80% by weight of calcium sulfate half-hydrate and 85-20% by weight of water, an aqueous solution, an aqueous dispersion, or an aqueous suspension; and stirring the resulting mixture into a paste having a viscosity in the range of 20 and 75 poises. The paste is injected into a cavity of a bone or a vertebra to be reinforced. U.S. Pat. No. 6,251,139 discloses addition of drugs or nutrients before the mixing or in the midst of the mixing such that they are mixed with the calcium sulfate half-hydrate and water, the aqueous solution, the aqueous dispersion or the aqueous suspension provided. Further it is stated that such drugs and nutrients added should not have adverse effect on the hardening of the paste. After mixing the resulting paste is rested for a period of time to have a desired viscosity.
It is an object of the invention to provide an inorganic bone mineral substitute composition comprising an additive having a desired effect, said additive having a retarding or strong retarding effect on the hardening of the inorganic bone mineral substitute composition when admixed together with an aqueous liquid for hardening of the cement composition without sacrificing the rate of setting, the completion of the hydration of CSH into CSD or the properties of the final product (after 30 minutes) which is important for the clinical use thereof and of special importance in environments having a high blood flow to reduce the risk of leakage and risk of ingress in the blood vessels, which may cause an embolus.
It is also an object of the invention to provide an inorganic bone mineral substitute composition comprising an additive having a desired effect, said additive having a retarding effect on the hardening of the inorganic bone mineral substitute composition without changing the composition of bone mineral substitute by adding further chemicals.
It is a further object of the invention to provide an inorganic bone mineral substitute composition comprising an additive having a desired effect, said additive having, as a side effect, a retarding or strong effect on the hardening of the inorganic bone mineral substitute composition which may be applied shortly after mixing without delay which would else prolong the time needed for surgery and thus the occupancy of the operating room reducing the total capacity thereof and the potentially dangerous period under anaesthesia.